Azo sulfonamide derivatives



3,102,111 AZG SULFONAMIDE DERIVATIVES Gyiirgy (Isermely, Budapest,Gyiirgy Lugosi, Felsogod,

and Entire Jeney and Tihor Zsoluai, Dehreccn, Hungary, assignors toChinoin Gyogyszeres Vegyeszeti Termetrek Gyara R11, Budapest, Hungary"NoDravving. Filed Aug. 9, 1960, Ser. No. 48,34

Claims priority, application Hungary Aug. 17, 1959 g 6 Claims. (Cl.260-154)" I This invention relates to certain new pharmaceuticallyuseful sulfonamidederivatives and methods to prepare the same. a r

It has been found according tothe that compounds of the general formulapresent invention United States Patent (where R stands for a member ofthe group consisting of hydrogen and acyl, R stands for a member of the5 group consisting of thiazole, pyrimidine orpyridine ring and A standsfor an aromatic cycle) are valuable pharmaceuticals, respectively theymay be used as intermediates when preparing pharmaceuticals.The'compounds may be used successfully --when treating diseases causedby Staphylococcus aureus strains, which are resistant against hithertoknown sulphonamides and the greater part of which is resistant againstthe most antibiotics.

It is advantageous to employ these compounds when treating wounds e.-:g.in cases of fur-unculosis, impetigo, 'sycosis barbae, or when treatingWounds in postoperative cases especially when subcu'ration occurs, incases of j chr-onicus \otitis etc. whereby the compounds according to'the invention proved to beeffective antagonists of gram- 5, positivecocci. The compounds may be used as medicarnentswhen treating py'oderma,in cases of infections of the eyes, burns and generally to avoidinfections of wounds.. It is especially advantageous that the compoundsof the invention do not injure the eye respectively mucous membranes ofsensitive patients so that they may be used in the form of .ointments,Where other ointments could not be adapted.

The compounds according to the invention are efiectfiul againststrepto-, staphylo-, and pneumococci.

It is supposed, that thc acting mechanisms of these compounds differfrom those of known sulphonamides. The heterocycle may containsubstituents, such as j lower alkyl groups e.g. methyl-groups.Thedollowing compoundsare especially useful as anticoccidalpharmaceuticals': 2 (p amino benzene sulfonarnido) 4- Zenesultonarnido)4-methy1 5 (p methyl-phenyl+a zo)- thiazole, 2,- (p aminobenzene-sulfonamido) 4-phenylv 5 -,(p methyl phenyl azo) -tl1iazole.

'Ihe co npoundsaccording to the present invention may j be prepared byreacting compounds oi the formula (where R stands fora member of thegroup consisting of thiazo-le, pyrimidine and pyridine ring and-R standsfor amemb'er of the group consisting of hydrogen and acyl) withdiazotated aromatic amines. 1 As diazot'ated amines it is preferable touse diazotate aniline resp. aniline derivatives. Valuable products areobtained when V diazotated aniline, hallo'geno aniline,

alkoxy-aniline, or alkyl aniline is used. V Compounds of highanticoccidal activity are obtained when p-substituted 3,102,111'Patented Aug. 27, 1963 ice " derivatives, (such as, e. g., p-chloro-aniline) are employed.

The reaction is preferably carried out in an alkaline medium, e-.-g., inthe presence of alkali-hydroxides, am-

' ,moniumshydroxides, alkali or alkaline earth carbonates etc. c

It is preferable to use a diazotated amine which was prepared freshlybefore use and to add it in an aqueous solution to the aqueous solutionof the sulfonamide; The solution which contains the sulfonamide isadvantageously made alkaline before. By using this preferred methodtheproduct is obtained with excellent yields. The reaction may be'carriedout however in the presence of organic solvents as Well.

The compounds of this invention may be used in the form of woundsprayings, ointments for eyes, ointments for wounds, aqueoussuspensions, aerosols, and as enteresolvent ldragees.

The following ointment proved to be advantageous, e. g., tortreatrnentof the eyes:

2-(p-amino benzene sulfonamido) -4- 1nethyl-S- They also have an effecton strains of Staphylococcus aureus haemo- 2.53 g. of p-chloro-anilineare suspended in a solution of-7.5 ml. of water and 5.41111. of cone.hydrochloric acid. I After cooling with ice 1.4 g. of sodium nitrite areadded in aqueous solution, which was cooled with ice. Thereafter thereaction mixture is stirred for about 10 minutes. I p Y The solutionof-diazotated p-chloroaniline thus obtained is added under intensivestirring to an ice-cold solution of 5.4 g. of2-(perninobenzenesultonamido)- 4-methyl-thiazole in 10ml. of 30%sodiumhydroxide and v 16.5 .ml. of acetone. 'A dark red solution isformed which is filtered after decolorizing with charcoal.

After minutes a light-yellow product is precipitated Q on adjusting thepH value to 5.5 by means of acetic acid.

After an hour the product is filtered, washed with Water and-dried; 7.43-g. of 2-(p-aminobenzene-sultonamido)-4-methyl-5-(p-chlorophenyl-azo)-thiazole is obtained with ayieid or 90%.The product is light yellow. M.P.: 242243 C.

Analysis.S, percent '-15.88 (theory 15.72); N, percent=17.05 (theory17.20); v

This product shows a'tot-al inhibiting eifect on the growthofStaphylococcus aureus and Staphylococcus olb'us strains in'aconcentration of 1 gmole per 50,000

lit. It showsv a total inhibiting action on Staphylococcus aurcusstrains which are resistant on ot her sulfonamides and antibiotics in aconcentration of 1 tgmole per 50,000

, lit.

The following method was employed for the determination of anticoccidalactivityz' the compound was dissolved in aqueous sodium hydroxidesolution, whereupon different quantities of the solution thus obtainedwere admixed with a' bouillonegar melt. In separate glass cups aftersolidification the nutrient media were inoculated with Staphylococcusstrains and incubated at 37 C. tor 24 hours. Each experiment wasreproduced three times and only the identical results were accepted.

Example 2 1.87 g. aniline are dissolved in a solution of 50 ml. of waterand 5.4 ml. of concentrated hydrochloric acid. 1.4 g. of sodium-nitriteare then added in a solution of 30 ml. of water at a temperature of 2 C.while cooling with ice. The reaction mixture is stirred for aboutminutes.

The solution thus obtained, containing diazotated aniline-HCl is addedwhile stirring intensively to a solution of 5.4 'g. of 2-(paminobenzenesulfonamido)-4-methylthiazole in 100 mls. of 3% sodiumhydroxide. After some minutes 150 ml. of water are added to the solutionof orange colour and after some standing the reaction mixture is madeneutral with a 25% solution of acetic acid. On standing for an hour theproduct is filtered hy suction, washed with water and dried. 6.70 g. of2-(pamino henzene-sulfonamido)-4-methyl-5-(phenyl-azo)- thiazole areobtained with 90% yield. M.P.: 236 C.

Analysis.S, percent=17.5 (theory 17.14); N, percent=17.56 (theory18.76).

The product shows a total inhibiting action on the growth ofStaphylococcus aureus strains in a concentration of 1 'gmole per 50,000lit. and a total inhibiting'action on the growth of Staphylococcusauareus strains which are resistant to other sultonamides and most ofantibiotics in a concentration of 1 gmole/ 25,000 lit.

Example 3 2.15 g. of p-toluidene are dissolved in 50 ml. of water,containing 4.5 ml. of concentrated hydrochloric acid. The solution iscooled with ice whereupon 1.4 g. of sodium nitrite are added at atemperature hetween 0 C. and {+2 C. in a solution of 30 ml. of watercooled with ice.

After about 10 minutes of stirring the solution containing diazotatedp-toluidene-HCI is added to a, solution of 5.4 'g. of2-(p-arnino-benzene-sultonamido)-4-methylthiazole in 100 ml. of 3%sodium hydroxide. A solution of orange colour is formed. 150 ml. ofwater are added, whereupon the solution is made neutral by means oi? asolution of 25% acetic acid. A light yellow product precipitates, whichis filtered with suction, washed with water and dried. 7 :g. of2-(p-arnino-benzene-sul-foniamido)-4-methyl-5-(p-tolyl-azo)-thiazole areobtained. M.P.: 242243 C. The product may he recrystallized frommethanol.

Analysis-S, percent=16.99 (theory 1653); N, percent=17.56 (theory18.08).

The product shows a total inhibiting action on the growth of:

Strains Concentration 1 mole/sonooiit. 1 groom/50,000 lit. 1groom/50,000 lit.

Example 4 2.53 g. of p-zchloroaniline are diazotated in a solution of 50ml. of water and 5.4 ml. of concentrated hydrochloric acid with 1.4 g.of sodium nitrite, according to the method described in the previousexamples.

The solution obtained is added to a solution of 6.25 g. of 2 pacetylaminobenzene-sulfonamido)-4-methylthiazole and'100 ml. of 3% sodiumhydroxide. orange-red solution is formed. On addition of 150 ml. ofwater and neutralizing with a 25 solution of acetic acid a light yellowcoloured substance is precipitated. The product is filtered, washed withwater and dried. 5.9 g. of 2- (.p-acetyl-amino benzene-sulfonamido)-4-methyl-S-(p-chlorophenyl-azo)-thiazole is obtained. M.P.: 240 C.

hydroxide.

Strains 1 Concentration 1 gmole/5,000 lit.

Slap s aureus 1 guide/5,000 lit.

Staphylococcus aurcus resistant Example 5 2.53 g. of p-ohloroaniline arediazotated with 1.4 g. of sodium nitrite according to the methoddescribed in the previous examples.

The solution containing diazotated p-chloroaniline-l-lCl is added to asolution of 5.0 g. of pemino-benzene-sulfonamide-pyridine in ml. of a 3%solution of sodium A solution of orange-red colour is formed which istreated as described in Example 1, whereupon 6.1 g. of2-(p-amino-benzene-sulfonamido)-5-(p-chlorophenyl-azo)-pyridine areobtained. M.P.: 170 C. (decomp.).

The product shows a total inhibiting action On the growth of:

Strains Concentration Staphylococcus aureus 1 mole/2,500 lit. Slaphy cmaurcus r t 1 gmole/LOOO lit.

Example 6 Strains Concentration 1 gmole/5,000 lit.

Staphylococcus aurcus 1 gmolc/1,000 lit.

Staphylococcus ourcua resistant Example 7 2.74 g. of p-ethoxy-a'nilineare diazotated as described in the previous examples with 1.4 g. ofsodium nitrite. The solution containing diazotated p-ethoxy-aniline-HCIis added to a solution of 5.4 g. ofZ-(p-amino-benzenesulfonamido)-4-metl1yl-thi-azo1e 100 ml. of a 3%aqueous sodium hydroxide solution. ml. of water are added to thesolution thus obtained, whereupon the solution is made neutral with a25% aqueous acetic acid solution. The precipitate is filtered, washedwith water and dried. 7.0 g. of 2-(p-amino-benzeue-sulfonamido)-4-methyl-5-(p-ethoxy-phenyl-azo) thiazole are obtained. The product maybe purified by heating with a great excess of methanol. M.P.: 223-224"C. (decomp.).

The product shows a total inhibiting action on the growth of:

Strains Concentration "out 8 our-cur;

.c r 1 {uncle/50,000 lit. Staphylococcus aurcus resistant.

1 gmole/5,000 lit.

in the previous Examples with 1.4 g. of sodium nitrite.

Strains Concentration Stags v aureus- 1 guide/25.000 lit. Staphylococcusaureus resistant 1 guide/5,000 lit.

Example 9 2.53 g. of p-chloro-aniline is mixed with 50 of Watercontaining 5.4 ml. of cone. hydnochloric acid, whereupon diazotation iscarried :out as described in the previous examples. The solutioncontaining diazotated p-chloro-aniline is added to a solution of 5.1 g.of 2-(paminobenzene-sulfonamido) -thiazole in 100 ml. of a 3% aqueoussodium hydroxide solution. 150 ml. of Water is added to the solutionthus obtained, whereupon the solution is made neutral with an aqueousacetic acid solution. The precipitate is filtered, washed with water anddried. 6.75 g. of 2-(pamino-benzene-sulfionamido)-5-(p-chloro-phenyl-azo)-thiazole are obtained. The product may be purifiedby heating with a great excess of methanol. M.P.: 250 C. (decomp).

The product shows a total inhibiting action on the growth of:

Strains Concentration Staphylococcus aureus 1 groom/2,500 lit.

Example 2.15 g. of toluidene are diazotated as described in the previousexamples with 1.4 g. of sodium nitrite. The solution thus obtained isadded to a solution of 6.84 g. ofZ-(paminobeuzene-sulionamido)-4pheny1-thiazole in 100 ml. of a 3%aqueous sodium hydroxide solution. 150 ml. of Water are added to thesolution, whereupon the solution is made neutral with dilutedhydrochloric acid. The precipitate is filtered, Washed withwater anddried. 7.8 g. of 2-(p-amino-benzene-sulionamido)-4-phenyl-S-(p-tolyl-azo)athiazole are obtained. The ptDOduct may bepurified by heating with a great excess of methanol. M.P.: ISO-151 C.

The product shows a total inhibiting action on the growth of:

6 We claim: 1. Compounds of the fiormula R1NH SO2-NIE[ RN=NA wherein Ris selected from a member of the group consisting of hydrogen atom andacetyl group, R is a member of the group consisting of the followingresidues and A is a member of the group consisting OEE a phenyl,

p methylphenyl, p-ethoxyphenyl, p-chlorophenyl and otnapthyl.

2. The compound of the formula HHN 01 lfiT--(||]CH3 SO2NH-C CN=N 3. Thecompound of the formula H2N- CH3 II ICCHa SO2NHO 0-N=N- s 4. Thecompound of the iormula CHa-C O-NH 01 1 I--(H1-oH3 SOaNH-C CNN s 5. Thecompound of the formula H2N- Cl I 1 1 11 S02NHO CN=N- 6. The compound ofthe formula l lfiI(fi-CH3 SO2NHC|} -N=N- N=C CH3 References Cited in thefile of this patent UNITED STATES PATENTS 1,856,602 Tisza et a1. May 3,1932 1,990,923 Tisza et a1 Feb. 12, 1935 2,307,650 Tisza et a1 Jan. 5,1943 2,430,439 Winnek et a1. Nov. 4, 1947

1. COMPOUNDS OF THE FORMULA